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- PDB-8akc: Human Sirt6 in complex with ADP-ribose and fragment 3-(acetylamin... -

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Basic information

Entry
Database: PDB / ID: 8akc
TitleHuman Sirt6 in complex with ADP-ribose and fragment 3-(acetylamino)thiophene-2-carboxylic acid
ComponentsNAD-dependent protein deacetylase sirtuin-6
KeywordsHYDROLASE / Deacylase / Fragment
Function / homology
Function and homology information


NAD-dependent histone H3K56 deacetylase activity / NAD-dependent histone H3K18 deacetylase activity / ketone biosynthetic process / NAD-dependent histone H3K9 deacetylase activity / protein delipidation / regulation of lipid catabolic process / NAD+- protein-lysine ADP-ribosyltransferase activity / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / chromosome, subtelomeric region ...NAD-dependent histone H3K56 deacetylase activity / NAD-dependent histone H3K18 deacetylase activity / ketone biosynthetic process / NAD-dependent histone H3K9 deacetylase activity / protein delipidation / regulation of lipid catabolic process / NAD+- protein-lysine ADP-ribosyltransferase activity / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / chromosome, subtelomeric region / pericentric heterochromatin formation / NAD+-protein-arginine ADP-ribosyltransferase activity / positive regulation of protein localization to chromatin / DNA damage sensor activity / positive regulation of stem cell differentiation / positive regulation of blood vessel branching / NAD-dependent protein lysine deacetylase activity / protein localization to site of double-strand break / retrotransposon silencing / protein acetyllysine N-acetyltransferase / cardiac muscle cell differentiation / NAD-dependent histone deacetylase activity / positive regulation of chondrocyte proliferation / positive regulation of telomere maintenance / protein deacetylation / negative regulation of glucose import / TORC2 complex binding / lncRNA binding / negative regulation of glycolytic process / negative regulation of protein localization to chromatin / DNA repair-dependent chromatin remodeling / positive regulation of double-strand break repair / positive regulation of vascular endothelial cell proliferation / negative regulation of gene expression, epigenetic / regulation of double-strand break repair via homologous recombination / negative regulation of protein import into nucleus / positive regulation of stem cell population maintenance / positive regulation of stem cell proliferation / regulation of protein secretion / negative regulation of transcription elongation by RNA polymerase II / site of DNA damage / NAD+-protein ADP-ribosyltransferase activity / negative regulation of cellular senescence / subtelomeric heterochromatin formation / regulation of lipid metabolic process / NAD+ ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / nucleosome binding / NAD+ binding / positive regulation of fat cell differentiation / negative regulation of gluconeogenesis / pericentric heterochromatin / regulation of protein localization to plasma membrane / response to UV / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / nucleotidyltransferase activity / positive regulation of protein export from nucleus / determination of adult lifespan / circadian regulation of gene expression / base-excision repair / protein destabilization / regulation of circadian rhythm / positive regulation of insulin secretion / chromatin DNA binding / Pre-NOTCH Transcription and Translation / transcription corepressor activity / positive regulation of fibroblast proliferation / double-strand break repair / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / glucose homeostasis / site of double-strand break / positive regulation of cold-induced thermogenesis / Processing of DNA double-strand break ends / damaged DNA binding / chromatin remodeling / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / chromatin binding / chromatin / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / protein homodimerization activity / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / DHS-like NAD/FAD-binding domain superfamily
Similarity search - Domain/homology
Chem-AR6 / 3-(acetylamino)thiophene-2-carboxylic acid / DI(HYDROXYETHYL)ETHER / NAD-dependent protein deacylase sirtuin-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.83 Å
AuthorsYou, W. / Steegborn, C.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG) Germany
CitationJournal: To Be Published
Title: Development of novel Sirtuin 6 inhibitors and activators based on a protein crystallography-based fragment screen
Authors: You, W. / Steegborn, C.
History
DepositionJul 29, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-6
B: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,99021
Polymers67,2632
Non-polymers2,72719
Water2,180121
1
A: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,01311
Polymers33,6321
Non-polymers1,38110
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,97710
Polymers33,6321
Non-polymers1,3469
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.071, 91.071, 143.588
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number173
Space group name H-MP63
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: LYS / Beg label comp-ID: LYS / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: 1 / Auth seq-ID: 15 - 297 / Label seq-ID: 9 - 291

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.344085, -0.938911, 0.00725), (-0.938912, -0.344123, -0.004939), (0.007132, -0.005108, -0.999961)-0.22124, 0.24903, 61.318001

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein NAD-dependent protein deacetylase sirtuin-6 / Regulatory protein SIR2 homolog 6 / SIR2-like protein 6


Mass: 33631.594 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT6, SIR2L6 / Plasmid: pET151-D-TOPO / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2 (DE3) pLysS
References: UniProt: Q8N6T7, protein acetyllysine N-acetyltransferase

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Non-polymers , 7 types, 140 molecules

#2: Chemical ChemComp-AR6 / [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL [HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE / Adenosine-5-Diphosphoribose


Mass: 559.316 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H23N5O14P2
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-GV9 / 3-(acetylamino)thiophene-2-carboxylic acid


Mass: 185.200 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H7NO3S / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 121 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.6 Å3/Da / Density % sol: 52.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.7
Details: 1.6 M (NH4)2SO4, 10% PEG 400, and Bis-Tris buffer pH 5.7
PH range: 5.7-6.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.657
11-K, -H, -L20.343
ReflectionResolution: 1.83→45.54 Å / Num. obs: 59281 / % possible obs: 99.9 % / Redundancy: 6.9 % / Biso Wilson estimate: 37.779 Å2 / CC1/2: 0.995 / Rrim(I) all: 0.17 / Net I/σ(I): 7.25
Reflection shellResolution: 1.83→1.94 Å / Redundancy: 7.2 % / Mean I/σ(I) obs: 0.82 / Num. unique obs: 9567 / CC1/2: 0.345 / Rrim(I) all: 2.01 / % possible all: 99.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MF6

5mf6


Resolution: 1.83→45.54 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.953 / SU B: 1.848 / SU ML: 0.06 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.026 / ESU R Free: 0.023 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2063 2139 3.6 %RANDOM
Rwork0.1876 ---
obs0.1883 57141 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 96.08 Å2 / Biso mean: 38.294 Å2 / Biso min: 19.64 Å2
Baniso -1Baniso -2Baniso -3
1--14 Å2-0 Å2-0 Å2
2---14 Å2-0 Å2
3---28 Å2
Refinement stepCycle: final / Resolution: 1.83→45.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4360 0 159 121 4640
Biso mean--44.53 36.94 -
Num. residues----559
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0134606
X-RAY DIFFRACTIONr_bond_other_d0.0020.0144390
X-RAY DIFFRACTIONr_angle_refined_deg1.611.6576252
X-RAY DIFFRACTIONr_angle_other_deg1.2751.58110119
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.865555
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.41819.795244
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.71215764
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7741549
X-RAY DIFFRACTIONr_chiral_restr0.0820.2590
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.025045
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021019
Refine LS restraints NCSNumber: 2145 / Type: TIGHT THERMAL / Rms dev position: 4.89 Å / Weight position: 0.5
LS refinement shellResolution: 1.83→1.877 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.409 130 -
Rwork0.314 4206 -
all-4336 -
obs--99.52 %

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